Deletion of protein kinase D1 in pancreatic β-cells impairs insulin secretion in high-fat diet-fed mice


  • V. Bergeron
  • J. Ghislain
  • K. Vivot
  • N. Tamarina
  • L.H. Philipson
  • J. Fielitz
  • V. Poitout


  • Diabetes


  • Diabetes 67 (1): 71-77


  • Bβ-cell adaptation to insulin resistance is necessary to maintain glucose homeostasis in obesity. Failure of this mechanism is a hallmark of type 2 diabetes (T2D). Hence, factors controlling functional β-cell compensation are potentially important targets for the treatment of T2D. Protein kinase D1 (PKD1) integrates diverse signals in the β-cell and plays a critical role in the control of insulin secretion. However, the role of β-cell PKD1 in glucose homeostasis in vivo is essentially unknown. Using β-cell specific, inducible PKD1 knock-out mice (βPKD1KO), we examined the role of beta-cell PKD1 under basal conditions and during high-fat feeding. βPKD1KO mice under chow diet presented no significant difference in glucose tolerance or insulin secretion compared to mice expressing the Cre transgene alone; however, when compared to wild-type mice, both groups developed glucose intolerance. Under high-fat diet, deletion of PKD1 in β-cells worsened hyperglycemia, hyperinsulinemia and glucose intolerance. This was accompanied by impaired glucose-induced insulin secretion both in vivo in hyperglycemic clamps and ex vivo in isolated islets from high-fat fed βPKD1KO mice, without changes in islet mass. This study demonstrates an essential role for PKD1 in the β-cell adaptive secretory response to high-fat feeding in mice.